| HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. | |
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MedLine Citation:
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PMID: 19890330 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The activation of innate immune responses by nucleic acids is crucial to protective and pathological immunities and is mediated by the transmembrane Toll-like receptors (TLRs) and cytosolic receptors. However, it remains unknown whether a mechanism exists that integrates these nucleic-acid-sensing systems. Here we show that high-mobility group box (HMGB) proteins 1, 2 and 3 function as universal sentinels for nucleic acids. HMGBs bind to all immunogenic nucleic acids examined with a correlation between affinity and immunogenic potential. Hmgb1(-/-) and Hmgb2(-/-) mouse cells are defective in type-I interferon and inflammatory cytokine induction by DNA or RNA targeted to activate the cytosolic nucleic-acid-sensing receptors; cells in which the expression of all three HMGBs is suppressed show a more profound defect, accompanied by impaired activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-kappaB. The absence of HMGBs also severely impairs the activation of TLR3, TLR7 and TLR9 by their cognate nucleic acids. Our results therefore indicate a hierarchy in the nucleic-acid-mediated activation of immune responses, wherein the selective activation of nucleic-acid-sensing receptors is contingent on the more promiscuous sensing of nucleic acids by HMGBs. These findings may have implications for understanding the evolution of the innate immune system and for the treatment of immunological disorders. |
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Authors:
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Hideyuki Yanai; Tatsuma Ban; ZhiChao Wang; Myoung Kwon Choi; Takeshi Kawamura; Hideo Negishi; Makoto Nakasato; Yan Lu; Sho Hangai; Ryuji Koshiba; David Savitsky; Lorenza Ronfani; Shizuo Akira; Marco E Bianchi; Kenya Honda; Tomohiko Tamura; Tatsuhiko Kodama; Tadatsugu Taniguchi |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 462 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-05 Completed Date: 2009-12-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 99-103 Citation Subset: IM |
Affiliation:
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Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cytosol / immunology DNA / immunology HMGB Proteins / deficiency, genetics, immunology*, metabolism* HMGB1 Protein / deficiency, genetics, immunology, metabolism HMGB2 Protein / deficiency, genetics, immunology, metabolism Immunity, Innate / immunology* Interferon Regulatory Factor-3 / metabolism Mice Mice, Inbred C57BL Models, Immunological NF-kappa B / metabolism Nucleic Acids / immunology* Nucleotides / chemistry, immunology, metabolism RNA / immunology Signal Transduction Toll-Like Receptors / immunology Virus Diseases / immunology, virology |
| Chemical | |
Reg. No./Substance:
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0/HMGB Proteins; 0/HMGB1 Protein; 0/HMGB2 Protein; 0/Interferon Regulatory Factor-3; 0/Irf3 protein, mouse; 0/NF-kappa B; 0/Nucleic Acids; 0/Nucleotides; 0/Toll-Like Receptors; 63231-63-0/RNA; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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